Unsaturated derivatives of compounds of the cyclopentano polyhydro phenanthrene series and a process of producing the same



Patented May 14, 1940 UNITED STATES UNSATURATED DERIVATIVES OF COM- POUNDS OF THE CYCLOPENTANO POLY- HYDRO PHENANTHRENE SERIES AND A PROCESS OF PRODUCING THE SAME Adolf Bntenandt,

Berlin Lichterfelde, and

Friedrich Hildebrandt, Hohen Neuendori,

near Berlin, Germany,

Bloomfield, N. J., a corporation Corporation, of New Jersey No Drawing.

assignors to Schering Application December 22, 1936,

Serial No. 117,152. In Germany December 16 Claims. (Cl. 260-397) This invention relates to unsaturated derivatives of compounds of the cyclopentano polyhydro phenanthrene series and particularly to such derivatives wherein the carbon atom 17 bearing a substituent is combined with the neighbouring carbon atom by a carbon to carbon double bond, and to a process of producing the same.

Our invention relates in particular to the production of unsaturated cyclopentano polyhydro phenanthrene compounds belonging to the oestrane and etiocholane types and having a carbonto-carbon double bond at the 17-carbon. By oestrane type is to be understood those compounds whose ring A is aromatic in character, and in certain compounds also ring B, while the term etiocholane type embraces compounds in which all of the rings are partially or completely hydrogenated.

The process of the present invention consists in subjecting compounds of the cyclopentano polyhydro phenanthrene series which contain a tertiary hydroxyl group and a hydrocarbon substituent at the carbon atom 17 and a free hydrogen atom in the neighbourhood to the tertiary hydroxyl group present at the carbon atom 1'7, to a treatment suitable for splitting of! water.

Such treatments are described, for instance, in

Houben-Weyl, Methods of Organic Chemistry,

2nd vol., 2nd edition, Leipzig 1922, page 746 seq. Thus, the splitting 01? of water can be eflected, for instance, by heating the starting material in a high vacuum, by boiling with acetic acid, by warming with metal salts, such as copper sulphate, stannous chloride or the like, usually in vacuum.

The cyclopentano polyhydro phenanthrene I compounds which come into consideration as starting materials for the process of the present invention and which have the general structural formula.

the copending applications Serial No. 748,664 and Serial No. 8,842. As to the numeration of the carbon atoms, reference is had, for instance, to Fieser, The Chemistry of Natural Products Related to Phenanthrene, New York 1936, page 111.

The carbon to carbon double bond formed in the reaction product by splitting 011 water according to the present invention may be situated between the carbon atoms 16 and 17 as indicated below, for instance, in the dehydration product II derived from the l7-methyl-dihydro follicle hormone I; the double bond may, however, also be situated between the carbon atoms 17 and 20 if the hydrocarbon radical present at the carbon atom 17 of the starting material renders possible or supports the splitting off of water in this direction, as is illustrated, for instance, by the following structural formulas representing 17-ethylandrostendiol-3.17 (Formula III) and l'l-isopropyl-androstandiol-3J7 (Formula V) and the corresponding dehydration products (Formula 1V and Formula VI):

CH: CH: CH; on on; I fi/V M) no cm on on on on, 1 1 s 0H 3 1 gin --9 H n H0 no III IV H:C\ CH: Ho 0 H s H: on; cm on cm OH: 0 I/\ L/ H I E \J 110 nox/ v VI In the types of compounds represented by Formulas III and IV the nuclear double bond may be present also between thecarbon atoms 4 and 5 instead of between 5 and 6.

If in the starting material besides the hydroxyl group situated at the carbon atom 17 one or more further hydroxyl groups are present, the latter can be transformed, if desired, by esterification, etherification or the like into the corresponding substituted compounds before carrying out the process of the present invention; in this manner the reaction products are obtained in the form of their substituted compounds used as starting materials, wherefrom the'free unsaturated compounds can be obtained by hydrolysis. On the other hand, the reaction products obtained according to the process of the present invention that have a free hydroxyl group can be transformed into the corresponding substituted compounds by esterification, etheriflcation or the like.

The following examples serve to illustrate the process of the present invention without, however, limiting the same to them:

Example 1 160 mg. l7-methyl dihydro follicle hormone of M. P. 185-187 C. are heated to boiling under reflux with 40 cos. of glacial acetic acid for 5 hours. Thereupon the acetic acid is distilled off in vacuum and the residue sublimated in a high vacuum. The fraction distilling over at C. is recrystallised from dilute methanol; the crystals obtained melt at 157-l59 C., the results obtained in the carbon hydrogen determination correspond to the formula 019K240.

Example 2 100 mg. l7-ethyl-androstenol-l'I-one-3, which can be obtained, for instance, from l'7 -ethylandrostendiol-3.l'l-dibromide. By oxidation by means of chromic acid anhydride and dehalogenation by means of zinc dust in weakly mineral acidic alcohol, are distilled in high vacuum at 80-90 C. The oil present in the receiver after 24 hours is recrystallised from acetone whereby crystals in the form of well shaped long needles of the M. P. C. are obtained, representing a keto group containing dehydration product of the formula CmHaoO. By reaction with semicarbazide acetate in alcoholic solution asemicarbazone can be produced therefrom which shows after recrystallisation from alcohol a melting point of about 225 C. (with decomposition).

Of course, various other modifications in the procedure of the process of the present invention may be resorted to within the scope of the appended claims without departing from the principles set forth herein.

The unsaturated derivatives of compounds of the cyclopentano polyhydro phenanthrene series obtainable according to the process of the present invention are valuable products in physiological respect as they can, for instance, serve as intermediate products for the production of physiologically active compounds.

What we claim is:

1. Process of producing unsaturated derivatives of compounds of the cyclopentano polyhydro phenanthrene series comprising subjecting compounds of the cyclopentano polyhydro phenanthrene series which contain a tertiary hydroxyl group and a hydrocarbon substituent at the carbon atom 17 and a hydrogen atom attached to a carbon atom adjacent to the tertiary hydroxyl group present at the carbon atom 1'7, dehydrating conditions whereby the elements of water are split oil from the substituents at the l'I-carbon and the adjacent carbon.

2. Process according to claim 1 characterise in that 17-methyl dihydro follicle hormone is used as starting material.

3. Process according to claim 1 characterised in that l'l-ethyl androstendiol-3.l7 is used as starting material.

4. Process according to claim 1 characterised in that 17-ethyl androstenol-1'7-one-3 is used as starting material.

5. Process according to claim 1 characterised in that a hydroxyl group present in the starti material besides the tertiary hydroxyl group situated at the carbon atom 1'1 is converted into a group that, upon hydrolysis, can be reconverted into a hydroxyl group.

6. Process according to claim 1 characterised in that a hydroxyl group present in the starting material besides the tertiary hydroxyl group situated at the carbon atom 17 is converted into a group that, upon hydrolysis, can be reconverted polyhydro phenanthrene series belonging to the etiocholane types and having the following structural formula wherein X represents a member of the group consisting of oxygen and an wherein X represents a member 01' the group consisting of oxygen and an group and R indicating a member of the class composed of the hydroxyl group and groups that, upon hydrolysis, can be replaced by a hydroxyl group.

11. Unsaturated compounds of the cyclopentano polyhydro phenanthrene series belonging to the etiocholane types and having the following structural formula wherein X represents a member of the group consisting of oxygen and an group and R indicating a member of the class com, posed of the hydroxyl group and groups that. upon hydrolysis, can be replaced by a hydroxyl group.

12. An unsaturated compound of the cyclopentano polyhydro phenanthrene series containing a keto group and having the general formula C21H30O corresponding to the structural formula CH; CH1

CH9 H said compound crystallising in the form of wellshaped long needles of the melting point C.,

its semi-carbazone melting at about 225 C. (with decomposition) 13. Process for producing unsaturated derivatives ofcompounds of the cyclopentano polyhydro phenanthrene series, comprising heating compounds of the cyclopentano polyhydro phenanthrene series, which contain a tertiary hydroxyl group and a hydrocarbon substituent at the carbon atom 17, and a hydrogen atom attached to a carbon atom adjacent to the tertiary hydroxyl group present at the carbon atom 17, under a high vacuum, until the elements of water are split oiT from the substituents at the 17-cartached to a carbon atom adjacent to the tertiary hydroxyl group present at the carbon atom 17, in the presence of a dehydrating agent, until the elements of water are split off from the substituents at the l7-carbon and the adjacent carbon.

16. Process for producing unsaturated derivatives of compounds of the cyclopentano polyhydro phenanthrene series, comprising heating compounds of the cyclopentano polyhydro phenanthrene series, which contain a tertiary hydroxyl group and a hydrocarbon substituent at the carbon atom 17, and a hydrogen atom attached to a carbon atom adjacent to the tertiary hydroxyl group present at the carbon atom 1'7, in the presence of acetic acid until the elements of water are split on from the substituents at the l'l-carbon and the adjacent carbon.

ADOLF BUTENAND'I'. FRIEDRICH HILDEBRANDT. 

